The CYP2C19 gene is mapped to chromosome 10 (10q24.1-q24.3) and contains nine exons that code for a microsomal protein consisting of 490 amino acids, CYP219 is expressed primarily in human liver, and to a smaller extent in several extra-hepatic tissues (e.g., gut-wall). Hepatic cytochrome P450 (CYP) 2C19 is an important enzyme in the metabolism of widely used drugs such as the proton pump inhibitors (omeprazole, esomeprazole, lansoprazole and pantoprazole), diazepam, phenyloin, proguanil, clopidogrel, voriconazole, nelfinavir and cyclophosphamide (Desta, Z. et al., Clin. Pharmacokinet., 41:913-58, 2002). As a result of genetic polymorphisms in the CYP2C19 gene and nongenetic factors (e.g. drug interactions), wide interindividual variability is seen in the in vitro as well as in vivo activity of CYP2C19. This variability accounts for a significant part of the substantial differences in the clearance and response to the large number of drugs metabolized by this enzyme. Therefore, identification of the mechanisms and causes for interindividual variability in CYP2C19 activity and developing means to prospectively predict them is important to optimize therapy with its substrates.
Conventional medical approaches to diagnosis and treatment of disease is based on clinical data alone, or made in conjunction with a diagnostic test. These traditional practices often lead to therapeutic choices that are not optimal for the efficacy of the prescribed drug therapy or to minimize the likelihood of side effects for an individual subject. Therapy-specific diagnostics (a.k.a., theranostics) is an emerging medical technology field that provides tests useful to diagnose a disease, choose the correct treatment regime, and monitor a subject's response. That is, theranostics are useful to predict and assess drug response in individual subjects, i.e., individualized medicine. Theranostic tests are useful to select subjects for treatments that are particularly likely to benefit from the treatment or to provide an early and objective indication of treatment efficacy in individual subjects, so that the treatment can be altered with a minimum of delay. Theranostic tests may be developed in any suitable diagnostic testing format, which include, but is not limited to, e.g., non-invasive breath tests, immunohistochemical tests, clinical chemistry, immunoassay, cell-based technologies, and nucleic acid tests.
There is a need in the art for a reliable theranostic test to define a subject's phenotype or the drug metabolizing capacity to enable physicians to individualize therapy thereby avoiding potential drug related toxicity in poor metabolizers and increasing efficacy. Accordingly, there is a need in the art to develop new diagnostic assays useful to assess the metabolic activity of drug metabolizing enzymes such as the cytochrome P450 enzymes (CYPs) in order to determine individual optimized drug selection and dosages.